Epidemiological studies provide compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) can significantly reduce the incidence and risk of death from multiple cancer types, including lung cancer. Unfortunately, the long-term use of NSAIDs for chemoprevention is not recommended because of toxicities associated with cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. However, numerous investigators have concluded that a COX-independent mechanism involving apoptosis induction is responsible for their antineoplastic activity, suggesting it may be feasible to develop safer and more efficacious derivatives by targeting the underlying pathway leading to apoptosis. From an extensive medicinal chemistry effort, we recently identified a novel sulindac derivative referred to as methoxy-sulindac sulfide amide (m-SSA) that potently and selectively inhibits lung tumor cell growth and induces apoptosis in vitro and tumor development in a mouse lung orthotopic model. Mechanistic studies revealed that m-SSA inhibits a specific phosphodiesterase (PDE) isozyme, PDE10 that is elevated in lung tumor cells and essential for their growth and survival. Oral administration of m-SSA was found to be well tolerated and can achieve high concentrations in lungs compared with plasma and other tissues. We hypothesize that m-SSA has unique advantages for lung cancer chemoprevention and propose studies to evaluate its efficacy, toxicity, and mechanism of action in a mouse model of chemical-induced lung tumorigenesis. Lung tumors will be analyzed for histopathology, drug levels, and used for in vivo mechanistic studies. These exploratory studies have high potential to impact human health by identifying a safe and efficacious clinical candidate for lung cancer chemoprevention as well as for the treatment of lung cancer.